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IL-7R AND C-KIT SIGNALING IN THYMOPOIESIS
by
Akira Toyama
___________________________________________________________________
A Dissertation Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CRANIOFACIAL BIOLOGY)
December 2008
Copyright 2008 Akira Toyama
Object Description
| Title | IL-7R and c-Kit signaling in thymopoiesis |
| Author | Toyama, Akira |
| Author email | atoyama@usc.edu; rz350lc@dslextreme.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Cranio-Facial Biology |
| School | School of Dentistry |
| Date defended/completed | 2008-10-22 |
| Date submitted | 2008 |
| Restricted until | Unrestricted |
| Date published | 2008-12-04 |
| Advisor (committee chair) | Lutzko, Carolyn |
| Advisor (committee member) |
Paine, Michael L. Le, Anh D. Shi, Songtao Crooks, Gay M. |
| Abstract | IL-7 and Kit ligand (KL) are cytokines produced by thymic epithelial cells, which interact with their cognate receptors on immature thymocytes. The IL-7R is comprised of the IL-7Rα and common γ chain (γc) and has no intrinsic kinase activity, while KL binds to the receptor tyrosine kinase Kit. Both IL-7Rα^-/- and IL-7^-/- mice have profound defects in thymopoiesis, although for unexplained reasons, the defects in differentiation and thymic cellularity are more severe for IL-7Rα -/- than IL-7-/- mice. In order to understand possible interactions between IL-7R and Kit signaling in vivo, we generated doubly mutated mice which were homozygous for the Kit^W41 loss of function mutation and null for either IL-7 or IL-7Rα. While IL-7^-/- and IL-7Rα^-/- mice had a 90-99% reduction in thymic cellularity and the Kit^W41/W41 mice had a 50% reduction, the IL-7-/-Kit^W41/W41 and IL-7Rα-/-Kit^W41/W41 mice had fewer than 200 thymocytes, representing a 5-6 log decrease in thymic cellularity. The thymocytes in the IL-7^-/-Kit^W41/W41 and IL-7Rα^-/-Kit^W41/W41 mice were blocked at the earliest recognizable stage of thymic differentiation. The frequency of early Tlineage progenitors (ETP) in IL-7Rα^-/-, IL-7^-/-Kit^W41/W41, and IL-7Rα^-/-Kit^W41/W41 mice was significantly reduced compared to parental strains or wild type mice. Introduction of a bcl-2 transgene did not relieve the block in differentiation of CD4- CD8- (DN) thymocytes, or reduction in ETP absolute numbers in IL-7Rα^-/-Kit^W41/W41 mice, but partially rescued IL-7Rα^-/- mice. Cytokeratin expression analysis showed that thymic epithelial cells (TEC) of IL-7^-/-Kit^W41/W41, and IL-7Rα^-/-Kit^W41/W41 mice were K8+K5+, indicating that differentiation of TEC was arrested in these mice. IL-7Rα^-/- Kit^W41/W41 transgenic bcl-2 thymuses had K8+K5- areas indicating that medullary areas developed. Conclusions: 1) IL-7R and Kit provide synergistic, partially redundant, and unique signals for thymocyte proliferation, ma |
| Keyword | thymopoiesis; cytokine signaling; T-lineage progenitors |
| Language | English |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m1872 |
| Rights | Toyama, Akira |
| Repository name | Libraries, University of Southern California |
| Repository address | Los Angeles, California |
| Repository email | http://www.usc.edu/isd/libraries/services/ask_a_librarian/email/ |
| Filename | etd-Toyama-2518 |
| Archival file | uscthesesreloadpub_Volume40/etd-Toyama-2518.pdf |
Description
| Title | Page 1 |
| Full text | IL-7R AND C-KIT SIGNALING IN THYMOPOIESIS by Akira Toyama ___________________________________________________________________ A Dissertation Presented to the FACULTY OF THE GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (CRANIOFACIAL BIOLOGY) December 2008 Copyright 2008 Akira Toyama |
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